P690: IDENTIFICATION OF CLINICALLY RELEVANT VARIANT-LEVEL SEX-BIAS IN SF3B1 K700/K666 AND IDH2 R140/R172
Authors: Maki Sakuma, Constance Baer, Manja Meggendorfer, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach, Wencke Walter
Journal: HemaSphere (2023)

Background: Sex dimorphism in cancer is widely recognized, and efforts are underway to incorporate sex information in therapy decisions and patient care. In hematological malignancies, a patient’s mutation profile is critical in establishing a personalized treatment plan. However, growing evidence implicates not only the mutated gene as clinically relevant but also the specific variant for which sex differences have not yet been fully analyzed. Aims: To comprehensively describe sex bias in driver genes of hematological malignancies at the variant level and evaluate their clinical relevance. Methods: We examined 109 driver genes of hematological malignancies in a cohort of 10,416 patients whose material was sent to MLL Leukemia Laboratory for diagnostic workup between Jan 2022 and Dec 2022 (median age 72, male 59%). The patients were grouped by the lineage of their diagnosis (WHO 2022), summing up to 9,841 myeloid malignancies (2,395 AML, 3,859 MDS, 1,085 CMML, 1,753 MPN and 785 other), 3,454 B cell malignancies, 156 T/NK cell malignancies, and 1,161 plasma cell malignancies. Variants with a frequency ≥ 5% in patients harboring a putative somatic variant and variant-diagnosis categories with at least 10 patients were included in the analysis. The percentage of male patients harboring the variant was compared to the percentage of male patients in the respective category or 50% (binomial test combined with Benjamini-Hochberg method). Survival data was analyzed in a previously published cohort of 753 MDS and 746 AML patients. Results: 113 variants in 54 genes were evaluated for sex bias in the routine cohort. 15 variants were significantly male-biased and 7 variants were significantly female-biased at least in one variant-diagnosis category (Figure A). Most male bias variants were consistent with previous reports, except for the so far unreported IDH2 R140 and SF3B1 K666. Similarly, SF3B1 K700 and IDH2 R172 variants have not been described as female-bias variants. SF3B1 K700 and IDH2 R172 variants in AML were female biased even assuming sex neutrality (male percentage 50%), and showed opposite trends from other variants of the same gene. To further describe the difference in sex bias in hotspot variants of the same gene, we compared the sex ratio of SF3B1 and IDH2 hotspot variants appearing in the diagnostic groups (Figure B). SF3B1 K666 variants tended to be male-biased in most categories, whereas SF3B1 K700 variants were neutral to female biased. IDH1 R132 and IDH2 R140 variants showed similar trends in sex-bias and occurred in various hematological malignancies, whereas IDH2 R172 variant occurred predominantly in AML with a female-bias. The variants of both genes are known to have prognostic difference, with SF3B1 K700E and IDH2 R172K having better prognosis. Unlike patients with low-risk MDS, such as MDS with isolated del5q, patients harboring SF3B1 K700E variants did not show worse prognosis in males, whereas males carrying K666 variants had a tendency to worse prognosis compared to females carrying K666 variants (Figure C). The group of males harboring IDH2 R172K variants was too small to perform survival analysis. Summary/Conclusion: This is the first comprehensive study to compare the sex ratio of driver genes at the variant level in a large cohort of hematological malignancies. Our findings extend the set of known sex-biased variant and support the hypothesis that male and female may have different mechanisms of oncogenesis, associated with potentially different outcomes, which needs to be further explored for precision medicine.Keywords: Somatic mutation, Mutation analysis, MDS/AML